This invention relates to the field of pharmacogenomics and specifically to the application of genetic polymorphism to diagnosing and treating diseases.
In nature, organisms of the same species usually differ from each other in some aspects, e.g., their appearance. The differences are genetically determined and are referred to as polymorphism. At many gene loci, two or more alleles may occur (genetic polymorphism). Genetic polymorphism is defined as the occurrence in a population of two or more genetically determined alternative phenotypes due to different alleles. Polymorphism can be observed at the level of the whole individual (phenotype), in variant forms of proteins and blood group substances (biochemical polymorphism), morphological features of chromosomes (chromosomal polymorphism) or at the level of DNA in differences of nucleotides (DNA polymorphism).
Polymorphism may play a role in determining individual differences in the response to drugs. Cancer chemotherapy is limited by the predisposition of specific populations to drug toxicity or poor drug response (14). Thus, for example, pharmacogenetics (the effect of genetic differences on drug response) has been applied in cancer chemotherapy to understand the significant inter-individual variations in responses and toxicities to the administration of anti-cancer drugs, which may be due to genetic alterations in drug metabolizing enzymes or receptor expression. See co-pending U.S. application Ser. No. 09/715,764.
Polymorphism is also associated with cancer susceptibility (oncogenes, tumor suppressor genes and genes of enzymes involved in metabolic pathways) of individuals. In patients younger than 35 years, several markers of increased cancer risk have been identified. For example, prostate specific antigen (PSA) can be used for the early detection of prostate cancer in asymptomatic younger males, while particular cytochrome P4501A1 and gluthathione S-transferase M1 genotypes influence the risk of developing prostate cancer in younger patients. Similarly, mutations in the tumor suppressor gene, P53, are associated with brain tumors in young adults.
However, heretofore, polymorphism has not been associated with diagnosis and treatment of colorectal cancer. Presently, the assessment of the risk of developing colorectal cancer and diagnosis of colorectal cancer are carried out using screening methods in correlation with family history/relatives, proliferation assay and endoscopic screening. Advances in early diagnosis, screening procedures of high-risk individuals, the surgical approach and adjuvant therapy have not significantly impacted the prognosis of colorectal cancer in the last few decades. Thus, there exists a present need to develop more efficient methods and procedures for early diagnosis and treatment of colorectal cancer.
The invention provides a method for determining the colorectal cancer susceptibility of a patient comprising determining a patient""s genotype at the manganese superoxide dismutase (MnSOD) gene locus, wherein a patient with one or two alleles encoding alanine at position xe2x88x929 of the MnSOD signal peptide has an increased risk of developing colorectal cancer. Also provided are nucleic acid probes and kits for determining a patient""s colorectal cancer risk.
In one embodiment, the invention comprises the use of the allelic variant of the polymorphic region of the MnSOD gene. These methods of use include prognostic, diagnostic, and therapeutic methods. For example, the methods include using nucleic acids encompassing the polymorphic region as probes or primers to determine whether a subject has or is at risk of developing colorectal cancer. Accordingly, the invention provides methods for predicting or diagnosing colorectal cancer associated with an aberrant MnSOD gene activity.
In another embodiment, the invention provides a kit for amplifying and/or for determining the molecular structure of at least a portion of the MnSOD gene, comprising a probe or primer capable of hybridizing to the MnSOD gene and instructions for use. In one embodiment, the probe or primer is capable of hybridizing to an allelic variant of the MnSOD gene. In a preferred embodiment, the polymorphic region is located at position 351 of SEQ ID NO: 1. In a preferred embodiment, the invention provides a kit for determining whether a subject has or is at risk of developing colorectal cancer.
Other features and advantages of the invention will be apparent from the following detailed description and claims.